U.S. patent application number 14/347071 was filed with the patent office on 2014-12-04 for use of il-1 beta binding antibodies.
This patent application is currently assigned to Novartis AG. The applicant listed for this patent is Michael Shetzline, Tom Thuren, Andrew Zalewski. Invention is credited to Michael Shetzline, Tom Thuren, Andrew Zalewski.
Application Number | 20140356356 14/347071 |
Document ID | / |
Family ID | 47045163 |
Filed Date | 2014-12-04 |
United States Patent
Application |
20140356356 |
Kind Code |
A1 |
Thuren; Tom ; et
al. |
December 4, 2014 |
Use of IL-1 beta Binding Antibodies
Abstract
The present invention relates to an IL-1.beta. binding antibody
or a functional fragment thereof for use in preventing or reducing
risk of experiencing a recurrent cardiovascular (CV) event or a
cerebrovascular event in a patient that has suffered of a
qualifying CV event.
Inventors: |
Thuren; Tom; (Succasunna,
NJ) ; Zalewski; Andrew; (Elkins Park, PA) ;
Shetzline; Michael; (Randolph, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Thuren; Tom
Zalewski; Andrew
Shetzline; Michael |
Succasunna
Elkins Park
Randolph |
NJ
PA
NJ |
US
US
US |
|
|
Assignee: |
Novartis AG
Basel
CH
|
Family ID: |
47045163 |
Appl. No.: |
14/347071 |
Filed: |
September 27, 2012 |
PCT Filed: |
September 27, 2012 |
PCT NO: |
PCT/US2012/057444 |
371 Date: |
March 25, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61541341 |
Sep 30, 2011 |
|
|
|
Current U.S.
Class: |
424/133.1 ;
424/142.1; 424/158.1; 530/389.2 |
Current CPC
Class: |
C07K 16/245 20130101;
A61K 2039/505 20130101; A61P 9/10 20180101; C07K 2317/21 20130101;
A61K 2039/545 20130101 |
Class at
Publication: |
424/133.1 ;
424/158.1; 424/142.1; 530/389.2 |
International
Class: |
C07K 16/24 20060101
C07K016/24 |
Claims
1-71. (canceled)
72. A method of preventing or reducing risk of experiencing a
recurrent cardiovascular (CV) event or a cerebrovascular event in a
patient that has suffered of a qualifying CV event, comprising
administering about 25 mg to about 300 mg of an IL-1.beta. binding
antibody or functional fragment thereof, wherein said patient has a
hsCRP level of .gtoreq. about 1 mg/L before administration of said
antibody or functional fragment thereof.
73. The method according to claim 72, wherein said CRP level is
.gtoreq. about 2 mg/L.
74. The method according to claim 72, wherein said IL-1.beta.
binding antibody or functional fragment thereof 2-5 weeks from the
qualifying CV event.
75. The method according to claim 72, wherein said IL-1.beta.
binding antibody or functional fragment thereof is administered 3
years post a CABS (Coronary Artery Bypass Graft) procedure
regardless of timing of a qualifying CV event.
76. The method according to claim 72, wherein said IL-1.beta.
binding antibody or functional fragment thereof is administered
every 2 weeks, monthly, every 6 weeks, every 2 months, every 3
months, every 5 months, or every 6 months from the first
administration.
77. The method according to claim 72, wherein said recurrent CV
event is selected from the group consisting of cardiovascular
death, and myocardial infarction (Mi).
78. The method according to claim 72, wherein said recurrent CV
event is selected from the group consisting of hospitalization for
unstable angina, acute coronary syndrome, other non-coronary
ischemic event (transient ischemic attack or limb ischemia), any
revascularization procedure (coronary and non-coronary), limb
amputation, stent thrombosis (definite or probable),
hospitalization or prolongation of hospitalization for heart
failure, and coronary revascularization procedures (PCI or
CABG).
79. The method according to claim 72, wherein said cerebrovascular
event is stroke.
80. The method according to claim 72, wherein said qualifying CV
event is myocardial infarction.
81. The method according to claim 72, further comprising,
administering the patient an additional dose of about 25 mg to
about 300 mg of the IL-1.beta. binding antibody or functional
fragment thereof at week 2, week 4 or week 6 from the first
administration.
82. The method according to claim 72, wherein said method comprises
administering about 50 mg of the RA 0 binding antibody or
functional fragment thereof.
83. The method according to claim 72, wherein said method comprises
administering about 150 mg of the IL-1.beta. binding antibody or
functional fragment thereof.
84. The method according to claim 72, wherein said method comprises
administering about 300 mg of the IL-1.beta. binding antibody or
functional fragment thereof.
85. The method according to claim 72, wherein said method comprises
administering about 25, 75, 100, 125, 175, 200, 225, 250, 275, 300
mg or any combination thereof of the IL-1.beta. binding antibody or
functional fragment thereof.
86. The method according to claim 72, wherein said IL-1.beta.
binding antibody or functional fragment thereof is capable of
inhibiting the binding of IL-1.beta. to its receptor and has a
K.sub.D for binding to IL-1.beta. of about 50 pM or less.
87. The method according to claim 72, wherein said IL-1.beta.
binding antibody is selected from the group consisting of: a) an
IL-1.beta. binding antibody directed to an antigenic epitope of
human IL-1.beta. that includes a loop comprising the Glu64 residue
of the mature IL-1.beta., wherein said IL-1.beta. binding antibody
is capable of inhibiting the binding of to its receptor, and
further wherein said IL-1.beta. binding antibody has a K.sub.D for
binding to IL-1.beta. of about 50 pM or less: b) an IL-1.beta.
binding antibody that competes with the binding of an IL-1.beta.
binding antibody comprising a VH domain comprising SEQ ID NO:1 and
a VL domain comprising SEQ ID NO:2; c) an anti-IL-1.beta. binding
antibody comprising the three CDRs of SEQ ID NO:3, SEQ ID NO:4, SEQ
ID NO:5; d) an anti-IL-1.beta. binding a ibody comprising the three
CDRs of SEQ ID NO:6, SEQ ID NO:7 SEQ ID NO:8; e) an anti-IL-1.beta.
binding antibody comprising the three CDRs of SEQ IQ NO:3, SEQ ID
NO:4, SEQ ID NO:5 and the three CDRs of SEQ ID NO:6, SEQ ID NO:7,
SEQ ID NO:8; f) an anti-IL-1.beta. binding antibody comprising a VH
domain comprising SEQ ID NO:1; g) an anti-IL-1.beta. binding
antibody comprising a VL domain comprising SEQ ID NO:2; and h) an
anti-IL-1.beta. binding antibody comprising a VH domain comprising
SEQ ID NO:1 and a VL domain comprising SEQ ID NO:2.
88. The method according to claim 72, wherein said IL1.beta.
binding antibody is canakinumab.
89. The method according to claim 72, wherein said IL-1.beta.
binding antibody or functional fragment thereof is selected from
the group consisting of gevokizumab, LY-2189102 or AMG-108.
90. A pharmaceutical composition for preventing or reducing risk of
experiencing a recurrent cardiovascular (CV) event or a
cerebrovascular event in a patient that has suffered of a
qualifying CV event, wherein about 25 mg to about 300 mg of an
IL-1.beta. binding antibody or functional fragment thereof is to be
administered, and wherein said patient has a CRP level of .gtoreq.
about 1 mg/L before administration of said antibody or functional
fragment thereof.
Description
RELATED APPLICATIONS
[0001] The present disclosure claims priority to U.S. Provisional
Patent Application No. 61/541,341, filed Sep. 30, 2011, the
disclosure of which is incorporated by reference herein in its
entirety.
TECHNICAL FIELD
[0002] The present disclosure relates to novel uses and regimens
for preventing or reducing risk of experiencing a recurrent
cardiovascular (CV) event or a cerebrovascular event in a patient
that has suffered of a qualifying CV event, which employ an
IL-1.beta. binding antibody or functional fragments thereof, e.g.,
canakinumab.
BACKGROUND OF THE DISCLOSURE
[0003] Atherosclerosis is a disease characterized by chronically
high inflammatory state. Arterial inflammation and endothelial
dysfunction play key roles at all stages of the atherothrombotic
process. Inflammatory mediators are intimately implicated with the
cascade of events leading to atherosclerotic plaque initiation,
progression and rupture. Vascular endothelial cells express a
variety of adhesion molecules that recruit monocytes when
chronically exposed to noxious stimuli or pathological conditions.
Adverse conditions such as hyperlipidemia are associated with
enrichment of a pro-inflammatory subset of monocytes. These
monocytes apparently enter the intima under the influence of
chemotactic stimuli and engulf modified low density lipoprotein
(LDL) and cholesterol crystals (Duewell et al 2010). The material
internalized by phagocytes induces phagolysosomal damage and
subsequent leakage of contents into cytosol to activate
inflammasomes and caspase 1, and consequently the generation of
interleukin-1b (IL-1.beta.) from pro-interleukin-1.beta..
[0004] Interleukins are key mediators in the chronic vascular
inflammatory response in cardiovascular (CV) disease and have been
demonstrated in animal models and in humans to be potent modulators
of pro-inflammatory processes. The fact that these cytokines and
their receptors are highly expressed and are functional in almost
all cell types implicated in the pathogenesis of atherosclerosis
including smooth muscle cells, certain subset of macrophages and T
cells as well as endothelium support the role of interleukins in
vascular disease. For example, IL-1.beta. is a potent smooth muscle
cell mitogen, an activator of endothelial cells and increases extra
cellular matrix and collagen deposition, which plays a role in
plaque burden and arterial thickening. Furthermore, lack of
IL-1.beta. or ablation of IL-1 receptor has been shown to decrease
severity of atherosclerosis in apoE deficient mice. Thus,
antagonism of the IL-1.beta. mediated inflammation is a primary and
attractive target for ameliorating the vessel wall inflammation
associated with atherosclerosis.
[0005] WO2010/138939 generally relates to a method of treating
cardiovascular disorders with an IL-1.beta. antibody. However it
does not disclose a method of preventing or reducing risk of
recurrent CV events or a cerebrovascular event.
SUMMARY OF THE DISCLOSURE
[0006] Inflammation contributes to all phases of the
atherothrombotic process and patients with elevated inflammatory
biomarkers such as hsCRP have increased vascular risk. The present
disclosure relates, in part, to the finding that direct inhibition
of inflammation by administration of IL-1.beta. binding antibodies
will reduce cardiovascular event rates.
[0007] Accordingly, the present disclosure is directed to a method
of preventing or reducing risk of experiencing a recurrent
cardiovascular (CV) event or a cerebrovascular event in a patient
that has suffered of a qualifying CV event, comprising
administering about 25 mg to about 300 mg of an IL-1.beta. binding
antibody or functional fragment thereof, wherein said patient has a
level of hsCRP of about .gtoreq.1 mg/L before administration of
said antibody or functional fragment thereof.
[0008] Further features and advantages of the disclosure will
become apparent from the following detailed description of the
invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1: Risk of recurrent cardiovascular events in the PROVE
IT-TIMI 22 trial of acute coronary syndrome patients after
initiation of statin therapy, according to on-treatment levels of
hsCRP. Adapted from Ridker P M, Cannon C P, Morrow D, Rifai N, Rose
L M, McCabe C H, Pfeffer M A, Braunwald E. C-reactive protein
levels and outcomes after statin therapy. N Engl J Med 2005;
352:20-8.
[0010] FIG. 2: Balancing the IL-1.beta. system and its
contributions to human disease. IL-1.beta.=interleukin-1 beta;
IL-1R=interleukin-1 receptor; IL-1Ra=interleukin-1 receptor
antagonist; CAPS=cryopyrin-associated periodic syndrome;
MWS=Muckle-Wells Syndrome; NOMID=neonatal-onset multi-system
inflammatory disease.
[0011] FIG. 3: hsCRP lowering by canakinumab in gout patients
supports quarterly dosing regimen (study H2251): the figure shows
hsCRP lowering by a single canakinumab dose is durable for 3 months
(85 days).
[0012] ACZ=ACZ885=canakinumab
[0013] Colch=colchicine
[0014] FIG. 4: Quarterly dosing regimen is supported by study
CACZ885A2213 data on patients with T2DM. X axis indicates time in
days (d)
[0015] FIG. 5: Multiple lines of evidence confirm dose and regimen
selection increasing confidence and biological plausibility.
[0016] FIG. 6: Phase II study data on hsCRP response supports
selection of 15 and 50 mg monthly doses of canakinumab [0017]
Biological activity of canakinumab can be monitored using hsCRP as
a surrogate [0018] Canakinumab dose selection based on primary
analysis data from study 12202 (5 to 150 mg vs. placebo monthly, 16
weeks, N=524): [0019] Safety (general safety and lipid effects)
[0020] hsCRP lowering dose response characteristics [0021] 15 mg
monthly dose of canakinumab was selected as a sub-maximal dose (30%
hsCRP lowering and 95% upper CI<0) [0022] 50 mg monthly dose of
canakinumab as maximally efficacious dose (40% hsCRP lowering)
[0023] FIG. 7: The amino-terminal sequences of the heavy chain
variable domain (V.sub.H) and the corresponding DNA sequences of
canakinumab are given, in which the CDRs are shown in bold type and
leader sequence in italics.
[0024] FIG. 8: The amino-terminal sequences of the light chain
variable domain (V.sub.L) and the corresponding DNA sequences of
canakinumab are given, in which the CDRs are shown in bold type and
leader sequence in italics.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0025] The present invention provides, inter alia, methods of
preventing or reducing risk of experiencing a recurrent
cardiovascular (CV) event or a cerebrovascular event in a patient
that has suffered of a qualifying CV event, comprising
administering about 25 mg to about 300 mg of an IL-1.beta. binding
antibody or functional fragment thereof, wherein said patient has a
CRP level of .gtoreq. about 1 mg/L before administration of said
antibody or functional fragment thereof.
[0026] Canakinumab is a fully human monoclonal anti-human
IL-1.beta. antibody of the IgG1/k isotype, being developed for the
treatment of IL-1.beta. driven inflammatory diseases. It is
designed to bind to human IL-1.beta. and thus blocks the
interaction of this cytokine with its receptors. The antagonism of
the IL-1.beta. mediated inflammation using canakinumab in lowering
high sensitivity C-reactive protein (hsCRP) and other inflammatory
marker levels has shown an acute phase response in patients with
Cryopyrin-Associated Periodic Syndrome (CAPS) and rheumatoid
arthritis. This evidence has been replicated in patients with type
2 diabetes mellitus (T2DM) using canakinumab and with other
IL-1.beta. antibody therapies in development.
[0027] Atherosclerotic vascular disease is the primary cause of
morbidity and mortality in individuals with and without T2DM. The
progression of atherosclerosis from endothelial dysfunction to
vascular occlusion or to plaque rupture is the underlying mechanism
responsible for many debilitating and life-threatening diseases
such as MI, stroke and peripheral vascular disease (PVD). These
diseases occur at higher frequency in T2DM patients and continue to
increase despite use of current optimal therapies. There is also
higher mortality rate after first MI in patients with T2DM compared
to those without T2DM. Mortality associated with impaired glucose
tolerance is 1.96 times higher compared to normal glucose
tolerance. Thus, novel therapies that may improve vascular
function, decrease atherosclerotic burden, and translate to a
decrease in cardiovascular events would fill a significant unmet
medical need.
[0028] T2DM is also a disease that is characterized by a high
inflammatory state. Pre-clinical data suggests IL-1.beta. is of key
importance in the progressive functional impairment and destruction
of .beta.-cells in type 2 diabetes. Pancreatic .beta. cells secrete
IL-1.beta. in response to elevated glucose exposure promoting
further impairment of cellular viability via an autocrine action.
IL-1.beta. antagonism inhibits .beta. cell death, promotes .beta.
cell proliferation, potentiates .beta. cell glucose-induced insulin
secretion and improves insulin sensitivity. Blocking IL-1.beta.
activity with an IL-1 receptor antagonist as well as a neutralizing
IL-1.beta. antibody in clinical trials reduced HbAlc.
Neutralization of IL-1.beta. activity in the pancreatic islets is
thus emerging as an attractive target for the treatment and
prevention of type 2 diabetes. For T2DM prevention canakinumab's
primary direct action is expected to prevent the IL-1.beta.
mediated destruction of pancreatic .beta.-cells and thus prevent or
delay progression of disease, which to date is a completely unmet
need.
[0029] As demonstrated in a comprehensive 2010 meta-analysis of 54
prospective cohort studies, the inflammatory biomarker hsCRP is an
independent risk factor for future cardiovascular events that (a)
has a magnitude of effect similar to or larger than that of blood
pressure or cholesterol and (b) has long-term stability and
reproducibility at least as good as these widely-accepted risk
factors (Kaptoge et al 2010). Abundant clinical trial data further
demonstrate that persistent elevations of hsCRP are a major risk
factor of recurrent vascular risk following myocardial infarction;
for example, as demonstrated in the PROVE IT-TIMI 22 (Ridker et al
2005) and A-to-Z (Morrow et al 2006) trials. In both trials
patients with known vascular disease and persistent elevation of
hsCRP were at roughly double the risk for recurrent events compared
to those with normal hsCRP levels. Further, stratification by hsCRP
has proven highly effective in determining populations in who added
cardiovascular benefits are observed with the use of efficacious
lipid lowering agents, which also possess anti-inflammatory
properties. This has been proven in primary prevention studies as
including the AFCAPS/TexCAPS (Ridker et al 2001) and JUPITER trials
(Ridker et al 2008, Ridker et al 2009) as well as in the setting of
congestive heart failure (CHF) in the CORONA trial where efficacy
of intervention was seen only among those with hsCRP.gtoreq.2 mg/L.
Indeed, in this latter example, had stratification been done by
hsCRP on an a priori basis, the trial would have been reported out
as an overwhelming positive rather than as a null finding (McMurray
et al 2009).
[0030] A direct anti-inflammatory agent could, in theory, be
effective at any stage of the atherothrombotic process. However,
the most appropriate population for a treatment with such an agent
is one in which (a) patients are known to be at increased risk
despite current therapy, and (b) there is biochemical evidence of a
persistent heightened inflammatory response despite usual care.
Recognizing these constraints, a primary prevention population
would be infeasible due to the exceptionally large sample size
required and because an extremely low side effect profile is
typically required in that setting. In contrast, patients who have
survived a MI are clinically stable, and who have persistently
elevated hsCRP levels despite aggressive treatment are an optimal
population in which to undertake a test of the inflammatory
hypothesis of atherothrombosis. This population is no longer at
risk for plaque rupture due to altered wound healing, yet remains
at high risk for recurrent vascular events despite use of all
accepted therapies.
[0031] Canakinumab and other IL-1 beta inhibiting agents, in
particular other IL-1.beta. binding antibodies, will reduce the
risk of future occurrence of major cardiovascular events or
cerebrovascular events in patients with recent past myocardial
infarction (MI) by preventing IL-1.beta. mediated vascular wall
inflammation and endothelial dysfunction.
[0032] Canakinumab is disclosed in WO02/16436 which is hereby
incorporated by reference in its entirety.
[0033] In one embodiment, the present disclosure provides a method
of preventing or reducing risk of experiencing a recurrent
cardiovascular (CV) event or a cerebrovascular event in a patient
that has suffered of a qualifying CV event, comprising
administering about 25 mg to about 300 mg of an IL-1.beta. binding
antibody or functional fragment thereof, wherein said patient has a
CRP level of .gtoreq. about 1 mg/L before administration of said
antibody or functional fragment thereof.
[0034] In one embodiment of any method of the invention, said CRP
level is .gtoreq. about 2 mg/L.
[0035] In one embodiment of any method of the invention said CRP
level is .gtoreq. about 1, .gtoreq. about 1.1, .gtoreq. about 1.2,
.gtoreq. about 1.3, .gtoreq. about 1.4..gtoreq. about 1.5, .gtoreq.
about 1.6, .gtoreq. about 1.7, .gtoreq. about 1.8, .gtoreq. about
1.9, .gtoreq. about 2.0, .gtoreq. about 2.1, .gtoreq. about 2.2,
.gtoreq. about 2.3, .gtoreq. about 2.4, .gtoreq. about 2.5,
.gtoreq. about 2.6, .gtoreq. about 2.7, .gtoreq. about 2.8..gtoreq.
about 2.9, .gtoreq. about 3.0 mg/L.
[0036] In some embodiment of any method of the invention said CRP
level is 1-3 mg/L, or 1.5-2.5 mg/L, or 1.7-2.3 mg/L or 1.8-2.2 mg/L
or 1.9-2.1 mg/L.
[0037] In one embodiment of any method of the invention, said level
of CRP level is hsCRP level.
[0038] In one embodiment of any method of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is
administered 2-5 weeks from the qualifying CV event.
[0039] In other embodiments of any method of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is
administered 3 weeks or 21 days, 4 weeks or 1 month or 28 days, 5
weeks or 35 days, or 6 weeks or 42 days from the qualifying CV
event.
[0040] In one embodiment of any method of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is
administered 3 years post a CABG (Coronary Artery Bypass Graft)
procedure regardless of timing of a qualifying CV event.
[0041] In one embodiment of any method of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is
administered every 2 weeks, monthly, every 6 weeks, bimonthly
(every 2 months), quarterly (every 3 months), every 5 months, or
every 6 months from the first administration.
[0042] In one embodiment of any method of the invention, said
recurrent CV event is selected from the group consisting of
cardiovascular death, myocardial infarction (MI), or the
cerebrovascular event is stroke.
[0043] In one embodiment of any method of the invention, said
recurrent CV event is selected from the group consisting of acute
coronary syndrome, hospitalization for unstable angina, other
non-coronary ischemic event (transient ischemic attack or limb
ischemia), any revascularization procedure (coronary and
non-coronary), limb amputation, stent thrombosis (definite or
probable), hospitalization or prolongation of hospitalization for
heart failure, and coronary revascularization procedures (PCI or
CABG).
[0044] In one embodiment, any method of the invention further
comprises administering the patient an additional dose of about 25
mg to about 300 mg of the IL-1.beta. binding antibody or functional
fragment thereof at week 2, week 4 or week 6 from the first
administration.
[0045] In one embodiment, the invention provides a method of
preventing or reducing risk of experiencing a recurrent
cardiovascular (CV) event or a cerebrovascular event in a patient
that has suffered of a qualifying CV event, comprising
administering about 50 mg of an IL-1.beta. binding antibody or
functional fragment thereof 2-5 weeks from the qualifying CV event,
wherein said patient has a CRP level of .gtoreq. about 1 mg/L
before administration of said antibody or functional fragment
thereof, and further comprising administering the patient an
additional dose of about 50 mg of the IL-1.beta. binding antibody
or functional fragment thereof at week 2, week 4 or week 6 from the
first administration and followed by a quarterly administration
from the first administration.
[0046] In one embodiment, the invention provides a method of
preventing or reducing risk of experiencing a recurrent
cardiovascular (CV) event or a cerebrovascular event in a patient
that has suffered of a qualifying CV event, comprising
administering about 150 mg of an IL-1.beta. binding antibody or
functional fragment thereof 2-5 weeks from the qualifying CV event,
wherein said patient has a CRP level of .gtoreq. about 1 mg/L
before administration of said antibody or functional fragment
thereof, and further comprising administering the patient an
additional dose of about 150 mg of the IL-1.beta. binding antibody
or functional fragment thereof at week 2, week 4 or week 6 from the
first administration and followed by a quarterly administration
from the first administration.
[0047] In one embodiment, the invention provides a method of
preventing or reducing risk of experiencing a recurrent
cardiovascular (CV) event or a cerebrovascular event in a patient
that has suffered of a qualifying CV event, comprising
administering about 300 mg of an IL-1.beta. binding antibody or
functional fragment thereof 2-5 weeks from the qualifying CV event,
wherein said patient has a CRP level of .gtoreq. about 1 mg/L
before administration of said antibody or functional fragment
thereof and followed by a quarterly administration from the first
administration.
[0048] In one embodiment, any method of the invention comprises
administering about 25, 75, 100, 125, 175, 200, 225, 250, 275, 300
mg or any combination thereof of the IL-1.beta. binding antibody or
functional fragment thereof. In other embodiments of the
administration regimens described above, a dose of about 25, 30,
35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110,
115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175,
180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240,
245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300 mg or
any combination thereof of said IL-1.beta. binding antibody or
functional fragment thereof can be administered.
[0049] In one embodiment of any method of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is an
IL-1.beta. binding antibody. In one embodiment of any method of the
invention, said IL-1.beta. binding antibody or functional fragment
thereof is capable of inhibiting the binding of IL-1.beta. to its
receptor and has a K.sub.D for binding to IL-1.beta. of about 50 pM
or less.
[0050] In other embodiments of any method of the invention said
IL-1.beta. binding antibody is selected from the group consisting
of: [0051] a) an IL-1.beta. binding antibody directed to an
antigenic epitope of human IL-1.beta. which includes the loop
comprising the G1u64 residue of the mature IL-1.beta., wherein said
IL-1.beta. binding antibody is capable of inhibiting the binding of
IL-1.beta. to its receptor, and further wherein said IL-1.beta.
binding antibody has a K.sub.D for binding to IL-1.beta. of about
50 .mu.M or less; [0052] b) an IL-1.beta. binding antibody that
competes with the binding of an IL-1.beta. binding antibody
comprising a VH domain comprising SEQ ID NO:1 and a VL domain
comprising SEQ ID NO:2; [0053] c) an IL-1.beta. binding antibody
comprising the three CDRs of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5;
[0054] d) an anti-IL-1.beta. binding antibody comprising the three
CDRs of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8; [0055] e) an
anti-IL-1.beta. binding antibody comprising the three CDRs of SEQ
ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and the three CDRs of SEQ ID
NO:6, SEQ ID NO:7, SEQ ID NO:8; [0056] f) an anti-IL-1.beta.
binding antibody comprising a VH domain comprising SEQ ID NO:1;
[0057] g) an anti-IL-1.beta. binding antibody comprising a VL
domain comprising SEQ ID NO:2; [0058] h) an anti-IL-1.beta. binding
antibody comprising a VH domain comprising SEQ ID NO:1 and a VL
domain comprising SEQ ID NO:2.
[0059] In one embodiment of any method of the invention, said
IL-1.beta. binding antibody or fragment thereof comprises the 3
CDRs of SEQ ID NO:1 are set forth in SEQ ID NO:3, 4, and 5 and
wherein the 3 CDRs of SEQ ID NO:2 are set forth in SEQ ID NO:6, 7,
and 8.
[0060] In other embodiments of any method of the invention, the
IL-1.beta. binding antibody comprises:
a) a VH having a first CDR having 0, 1 or 2 amino acid
substitutions in comparison to the CDR set forth in SEQ ID NO:3, a
second CDR having 0, 1 or 2 amino acid substitutions in comparison
to the CDR set forth in SEQ ID NO:3, a third CDR having 0, 1 or 2
amino acid substitutions in comparison to the CDR set forth in SEQ
ID NO:5; and b) a VL having a first CDR having 0, 1 or 2 amino acid
substitutions in comparison to the CDR set forth in SEQ ID NO:6, a
second CDR having 0, 1 or 2 amino acid substitutions in comparison
to the CDR set forth in SEQ ID NO:7, and a third CDR having 0, 1 or
2 amino acid substitutions in comparison to the CDR set forth in
SEQ ID NO:8, wherein said antibody has a K.sub.D for IL-1beta of 50
pM or less and wherein said antibody inhibits the binding of
IL-1.beta. to its receptor.
[0061] Substituted amino acids are ideally conservative
substitutions, and once substituted a skilled artisan could use an
assay such as those described in WO02/16436.
[0062] In one embodiment of any method of the invention, said
IL-1.beta. binding antibody is canakinumab. In other embodiments of
any method of the invention, said IL-1.beta. binding antibody or
functional fragment thereof is selected from the group consisting
of XOMA 052 or gevokizumab, LY-2189102 or AMG-108.
[0063] In some embodiments of any of the method described above,
the antibody or fragment binds to human IL-1.beta. with a
dissociation constant of about 50 pM or less. In some embodiments,
the antibody or fragment binds to human IL-1.beta. with a
dissociation constant of about 500 pM or less. In some embodiments,
the IL-1.beta. binding antibody or functional fragment thereof
binds to human IL-1.beta. with a dissociation constant of about 250
pM or less. In some embodiments, the IL-1.beta. binding antibody or
functional fragment thereof binds to human IL-1.beta. with a
dissociation constant of about 100 pM or less. In some embodiments
of any of the methods described above, the IL-1.beta. binding
antibody or functional fragment thereof binds to human IL-1.beta.
with a dissociation constant of about 5 pM or less. In some
embodiments, the IL-1.beta. binding antibody or functional fragment
thereof binds to human IL-1.beta. with a dissociation constant of
about 1 pM or less. In some embodiments, the IL-1.beta. binding
antibody or functional fragment thereof binds to human IL-1.beta.
with dissociation constant of about 0.3 pM or less.
[0064] In some embodiments of any and/or all of the methods
described above, the IL-13 binding antibody or functional fragment
thereof is a neutralizing antibody.
[0065] The canakinumab heavy chain variable region (VH) is set
forth as SEQ ID NO:1 of the sequence listing. CDR1 of the VH of
canakinumab is set forth as SEQ ID NO:3 of the sequence listing.
CDR2 of the VH of canakinumab is set forth as SEQ ID NO:4 of the
sequence listing. CDR3 of the VH of canakinumab is set forth as SEQ
ID NO:5 of the sequence listing.
[0066] The canakinumab light chain variable region (VL) is set
forth as SEQ ID NO:2 of the sequence listing. CDR1 of the VL of
canakinumab is set forth as SEQ ID NO:6 of the sequence listing.
CDR2 of the VL of canakinumab is set forth as SEQ ID NO:7 of the
sequence listing. CDR3 of the VL of canakinumab is set forth as SEQ
ID NO:8 of the sequence listing.
[0067] In some embodiments of any and/or all of the methods
described above, the anti-IL-1.beta. binding antibody or binding
fragment thereof competes with the binding of an antibody having
the light chain variable region of SEQ ID NO:1 and the heavy chain
variable region of SEQ ID NO:2.
[0068] FIG. 7 illustrates the sequence of VH and of the three
CDRs
[0069] In some embodiments, the disclosed methods comprise
administering an anti-IL-1.beta. binding antibody having the three
CDRs of SEQ ID NO:1. In further embodiments, the three CDRs of SEQ
ID NO:1 are set forth as SEQ ID NOs:3-5. In some embodiments, the
disclosed methods comprise administering an anti-IL-1.beta. binding
antibody having the three CDRs of SEQ ID NO:2. In further
embodiments, the three CDRs of SEQ ID NO:2 are set forth as SEQ ID
NOs:6-8.
[0070] FIG. 8 illustrates the sequence of VL and of the three
CDRs.
[0071] In some embodiments, the disclosed methods comprise
administering an anti-IL-1.beta. binding antibody having the three
CDRs of SEQ ID NO:1 and the three CDRs of SEQ ID NO:2. In further
embodiments, the three CDRs of SEQ ID NO:1 are set forth as SEQ ID
NOs:3-5 and the three CDRs of SEQ ID NO:2 are set forth as SEQ ID
NOs:6-8.
[0072] In some embodiments of any of the method described above,
said IL-1.beta. binding antibody or functional fragment thereof is
administered subcutaneously or intravenously.
[0073] When administered subcutaneously, canakinumab can be
administered in a reconstituted formulation comprising canakinumab
at concentration 10-150 mg/ml, 270 mM sucrose, 30 mM histidine and
0.06% polysorbate 80, wherein the pH of the formulation is 6.3-6.7,
preferably 6.5.
[0074] When administered subcutaneously, canakinumab can be
administered in a liquid formulation comprising canakinumab at
concentration: 10-150 mg/ml, 270 mM mannitol, 20 mM histidine and
0.04% polysorbate 80 (or polysorbate 20), wherein the pH of the
formulation is 6.3-6.7, preferably 6.5.
[0075] When administered subcutaneously, canakinumab or any of said
IL-1.beta. binding antibody or functional fragment thereof can be
administered to the patient in a liquid form or lyophilized form
for reconstitution contained in a prefilled syringe.
[0076] In other embodiments, any method of the invention, comprises
assessing patient reported outcomes which include tiredness,
physical function and performance function, comprising tiredness,
physical function and performance function, whereby said patient
reported outcomes (PRO) are improved by said method.
[0077] In other embodiments of any method of the invention, said
patient is concomitantly receiving standard of care treatment for
preventing or reducing risk of experiencing recurrent CV events.
Said standard of care treatment is a lipid lowering agent such as a
HMG-CoA reductase inhibitor, e.g., a statin such as lovastatin,
pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin,
mevastatin, pitavastatin, rosuvastatin or mixtures thereof or
mixtures with ezetimibe, niacin, amlodipine besylate),
anti-hypertensives such as a calcium channel blocker (e.g.,
amlodipine, diltiazem, nifedipine, nicardipine, verapamil) or
beta-adrenergic blocking drugs such as esmolol, metoprolol,
nadolol, penbutolol or anti-hypertensives such as labetalol,
metoprolol, hydralazine, nitroglycerin, nicardipine, sodium
nitroprusside, clevidipine or a diuretic such as a thiazide
diuretic, chlorthalidone, furosemide, hydrochlorothiazide,
indapamide, metolazone, amiloride hydrochloride, spironolactone,
triamterene, or an angiotensin-converting enzyme (ACE) inhibitor
such as ramipril, ramiprilat, captopril, lisinopril or an
angiotensin II receptor blocker such as losartan, valsartan,
olmesartan, irbesartan, candesartan, telmisartan, eprosartan or an
anticoagulant such as acenocoumarol, coumatetralyl, dicoumarol,
ethyl biscoumacetate, phenprocoumon, warfarin heparin, low
molecular weight heparin such as bemiparin, certoparin, dalteparin,
enoxaparin, nadroparin, parnaparin, reviparin, tinzaparin or an
inhibitor of platelet aggregation such clopidogrel, elinogrel,
prasugrel, cangrelor, ticagrelor, ticlopidine, cilostazol,
dipyridamole, picodamide eptiftbatide, abciximab, eptifibatide,
tirofiban or terutroban or a Prostaglandin analogue (PGI2) such as
beraprost, prostacyclin, iloprost or treprostinil, or COX
inhibitors such as aspirin, aloxiprin or carbasalate calcium,
indobufen or triflusal or cloricromen or ditazole or
1,3-Indandiones such as clorindione, diphenadione or phenindion, or
tioclomarol, or direct thrombin (II) inhibitors such as hirudin,
bivalirudin, lepirudin, desirudin (bivalent) or argatroban or
dabigatran (monovalent) or oligosaccharides such as fondaparinux,
idraparinux, or an heparinoids such as danaparoid, sulodexide,
dermatan sulfate or direct Xa inhibitors xabans such as apixaban,
betrixaban, edoxaban, otamixaban, rivaroxaban or REG1 or
defibrotide or ramatroban or antithrombin III or protein C
(drotrecogin alfa) or fibrinolytics plasminogen activators: r-tPA
such as alteplase, reteplase, tenecteplase or UPA such as urokinase
or saruplase) or streptokinase or anistreplase or monteplase or
other serine endopeptidases or ancrod or fibrinolysin; or brinase
or citrate or EDTA or oxalate or digitalis, or digoxin, or
nesiritide, or oxygen, or a nitrate such as glyceryl trinitrate
(GTN)/nitroglycerin, isosorbide dinitrate, isosorbide mononitrate
or an analgesic such as morphine sulfate or a renin inhibitor such
as aliskiren or an endothelin A receptor inhibitor or an
aldosterone inhibitor.
[0078] In other embodiments of any method according to the
invention, biomarkers other than hsCRP include but are not limited
to: IL-1Ra, IL-6, IL-18, leptin, adiponectin (total and high MW),
TNF.alpha., PAI-1 and fibrinogen.
[0079] In a particularly preferred embodiment, said IL-1.beta.
binding antibody is canakinumab.
[0080] In other embodiments, said IL-1.beta. binding antibody is
XOMA 052 or gevokizumab, LY-2189102 or AMG-108.
[0081] Other embodiments of the invention include:
[0082] An IL-1.beta. binding antibody or a functional fragment
thereof for use in preventing or reducing risk of experiencing a
recurrent cardiovascular (CV) event or a cerebrovascular event in a
patient that has suffered of a qualifying CV event, wherein
i) about 25 mg to about 300 mg of said IL-1.beta. binding antibody
or functional fragment thereof is to be administered, and wherein
ii) said patient has a CRP level of .gtoreq. about 1 mg/L before
administration of said antibody or functional fragment thereof.
[0083] Other embodiments of the invention include the use of an
IL-1.beta. binding antibody for the manufacture of a medicament
according to any of the described uses or methods herein.
[0084] In another embodiment the use of an IL-1.beta. binding
antibody is provided for the manufacture of a medicament for
preventing or reducing risk of experiencing a recurrent
cardiovascular (CV) event or a cerebrovascular event in a patient
that has suffered of a qualifying CV event, wherein
i) about 25 mg to about 300 mg of said IL-1.beta. binding antibody
or functional fragment thereof is to be administered, and wherein
ii) said patient has a CRP level of .gtoreq. about 1 mg/L before
administration of said antibody or functional fragment thereof.
[0085] In one embodiment of any use of the invention, said CRP
level is .gtoreq. about 2 mg/L. In one embodiment of any use of the
invention said CRP level is .gtoreq. about 1, .gtoreq. about 1.1,
.gtoreq. about 1.2, .gtoreq. about 1.3, .gtoreq. about 1.4..gtoreq.
about 1.5, .gtoreq. about 1.6, .gtoreq. about 1.7, .gtoreq. about
1.8, .gtoreq. about 1.9, .gtoreq. about 2.0, .gtoreq. about 2.1,
.gtoreq. about 2.2, .gtoreq. about 2.3, .gtoreq. about 2.4,
.gtoreq. about 2.5, .gtoreq. about 2.6, .gtoreq. about 2.7,
.gtoreq. about 2.8..gtoreq. about 2.9, .gtoreq. about 3.0 mg/L. In
some embodiment of any use of the invention said CRP level is 1-3
mg/L, or 1.5-2.5 mg/L, or 1.7-2.3 mg/L or 1.8-2.2 mg/L or 1.9-2.1
mg/L.
[0086] In one embodiment of any use of the invention, said level of
CRP level is hsCRP level.
[0087] In one embodiment of any use of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is to be
administered 2-5 weeks from the qualifying CV event.
[0088] In other embodiments of any use of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is to be
administered 3 weeks or 21 days, 4 weeks or 1 month or 28 days, 5
weeks or 35 days, or 6 weeks or 42 days from the qualifying CV
event.
[0089] In one embodiment of any use of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is to be
administered 3 years post a CABG (Coronary Artery Bypass Graft)
procedure regardless of timing of a qualifying CV event.
[0090] In one embodiment of any use of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is to be
administered every 2 weeks, monthly, every 6 weeks, bimonthly
(every 2 months), quarterly (every 3 months), every 5 months, or
every 6 months from the first administration.
[0091] In one embodiment of any use of the invention, said
recurrent CV event is selected from the group consisting of
cardiovascular death, myocardial infarction (MI), and the
cerebrovascular event can be stroke.
[0092] In one embodiment of any use of the invention, said
recurrent CV event is selected from the group consisting of
hospitalization for unstable angina, other non-coronary ischemic
event (transient ischemic attack or limb ischemia), any
revascularization procedure (coronary and non-coronary), limb
amputation, stent thrombosis (definite or probable),
hospitalization or prolongation of hospitalization for heart
failure, and coronary revascularization procedures (PCI or
CABG).
[0093] In one embodiment of any use of the invention, said patient
is to be administered an additional dose of about 25 mg to about
300 mg of the IL-1.beta. binding antibody or functional fragment
thereof at week 2, week 4 or week 6 from the first
administration.
[0094] In one embodiment, the invention provides an IL-1.beta.
binding antibody or functional fragment thereof for use in
preventing or reducing risk of experiencing a recurrent
cardiovascular (CV) event or a cerebrovascular event in a patient
that has suffered of a qualifying CV event, wherein
i) said patient has a CRP level of .gtoreq. about 1 mg/L before
administration of said antibody or functional fragment thereof, and
wherein ii) about 50 mg of said IL-1.beta. binding antibody or
functional fragment thereof is to be administered 2-5 weeks from
the qualifying CV event, and wherein iii) an additional dose of
about 50 mg of the IL-1.beta. binding antibody or functional
fragment thereof is to be administered at week 2, week 4 or week 6
from the first administration, and wherein iv) about 50 mg of said
IL-1.beta. binding antibody or functional fragment thereof is to be
quarterly (every 3 months) from the first administration.
[0095] In one embodiment, the invention provides an IL-1.beta.
binding antibody or functional fragment thereof for use in of
preventing or reducing risk of experiencing a recurrent
cardiovascular (CV) event or a cerebrovascular event in a patient
that has suffered of a qualifying CV event, wherein
i) said patient has a CRP level of .gtoreq. about 1 mg/L before
administration of said antibody or functional fragment thereof, and
wherein ii) about 150 mg of said IL-1.beta. binding antibody or
functional fragment thereof is to be administered 2-5 weeks from
the qualifying CV event, and wherein iii) an additional dose of
about 150 mg of the IL-1.beta. binding antibody or functional
fragment thereof is to be administered at week 2, week 4 or week 6
from the first administration.
[0096] In one embodiment, the invention provides an IL-1.beta.
binding antibody or functional fragment thereof for use in
preventing or reducing risk of experiencing a recurrent
cardiovascular (CV) event or a cerebrovascular event in a patient
that has suffered of a qualifying CV event, wherein
i) said patient has a CRP level of .gtoreq. about 1 mg/L before
administration of said antibody or functional fragment thereof, and
wherein ii) about 50 mg of said IL-1.beta. binding antibody or
functional fragment thereof is to be administered 2-5 weeks from
the qualifying CV event, and wherein iii) an additional dose of
about 50 mg of the IL-1.beta. binding antibody or functional
fragment thereof is to be administered at week 2, week 4 or week 6
from the first administration.
[0097] In one embodiment, any use of the invention, said patient is
to be administered about 25, 75, 100, 125, 175, 200, 225, 250, 275,
300 mg or any combination thereof of the IL-1.beta. binding
antibody or functional fragment thereof. In other embodiments of
the uses described above, said patient is to be administered about
25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,
105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165,
170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230,
235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295,
300 mg or any combination thereof of said IL-1.beta. binding
antibody or functional fragment thereof.
[0098] In one embodiment of any use of the invention, said
IL-1.beta. binding antibody or functional fragment thereof is an
IL-1.beta. binding antibody. In one embodiment of any use of the
invention, said IL-1.beta. binding antibody or functional fragment
thereof is capable of inhibiting the binding of IL-1.beta. to its
receptor and has a K.sub.D for binding to IL-1.beta. of about 50 pM
or less.
[0099] In other embodiments of any use of the invention said
IL-1.beta. binding antibody is selected from the group consisting
of: [0100] a) an IL-1.beta. binding antibody directed ton antigenic
epitope of human IL-1.beta. which includes the loop comprising the
Glu64 residue of the mature IL-1.beta., wherein said IL-1.beta.
binding antibody is capable of inhibiting the binding of IL-1.beta.
to its receptor, and further wherein said IL-1.beta. binding
antibody has a K.sub.D for binding to IL-1.beta. of about 50 pM or
less; [0101] b) an IL-1.beta. binding antibody that competes with
the binding of an IL-1.beta. binding antibody comprising a VH
domain comprising SEQ ID NO:1 and a VL domain comprising SEQ ID
NO:2; [0102] c) an anti-IL-1.beta. binding antibody comprising the
three CDRs of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5; [0103] d) an
anti-IL-1.beta. binding antibody comprising the three CDRs of SEQ
ID NO:6, SEQ ID NO:7, SEQ ID NO:8; [0104] e) an anti-IL-1.beta.
binding antibody comprising the three CDRs of SEQ ID NO:3, SEQ ID
NO:4, SEQ ID NO:5 and the three CDRs of SEQ ID NO:6, SEQ ID NO:7,
SEQ ID NO:8; [0105] f) an anti-IL-1.beta. binding antibody
comprising a VH domain comprising SEQ ID NO:1; [0106] g) an
anti-IL-1.beta. binding antibody comprising a VL domain comprising
SEQ ID NO:2; [0107] h) an anti-IL-1.beta. binding antibody
comprising a VH domain comprising SEQ ID NO:1 and a VL domain
comprising SEQ ID NO:2.
[0108] In one embodiment of any use of the invention, said
IL-1.beta. binding antibody or fragment thereof comprises the 3
CDRs of SEQ ID NO:1 are set forth in SEQ ID NO:3, 4, and 5 and
comprises the 3 CDRs of SEQ ID NO:2 are set forth in SEQ ID NO:6,
7, and 8.
[0109] In other embodiments of any use of the invention, said
IL-1.beta. binding antibody or functional fragment thereof
comprises:
a) a VH having a first CDR having 0, 1 or 2 amino acid
substitutions in comparison to the CDR set forth in SEQ ID NO:3, a
second CDR having 0, 1 or 2 amino acid substitutions in comparison
to the CDR set forth in SEQ ID NO:3, a third CDR having 0, 1 or 2
amino acid substitutions in comparison to the CDR set forth in SEQ
ID NO:5; and b) a VL having a first CDR having 0, 1 or 2 amino acid
substitutions in comparison to the CDR set forth in SEQ ID NO:6, a
second CDR having 0, 1 or 2 amino acid substitutions in comparison
to the CDR set forth in SEQ ID NO:7, and a third CDR having 0, 1 or
2 amino acid substitutions in comparison to the CDR set forth in
SEQ ID NO:8, wherein said antibody has a K.sub.D for IL-1beta of 50
pM or less and wherein said antibody inhibits the binding of
IL-1.beta. to its receptor.
[0110] Substituted amino acids are ideally conservative
substitutions, and once substituted a skilled artisan could use an
assay such as those described in WO02/16436.
[0111] In one embodiment of any use of the invention, said
IL-1.beta. binding antibody is canakinumab. In other embodiments of
any use of the invention, said IL-1.beta. binding antibody or
functional fragment thereof is selected from the group consisting
of XOMA 052 or gevokizumab (as disclosed in WO2007/002261,
incorporated by reference in its entirety), LY-2189102 or
AMG-108.
[0112] In some embodiments of any of the use described above, said
IL-1.beta. binding antibody or functional fragment thereof binds to
human IL-1.beta. with a dissociation constant of about 50 pM or
less. In some embodiments, the antibody or fragment binds to human
IL-1.beta. with a dissociation constant of about 500 pM or less. In
some embodiments, the IL-1.beta. binding antibody or functional
fragment thereof binds to human IL-1.beta. with a dissociation
constant of about 250 pM or less. In some embodiments, the
IL-1.beta. binding antibody or functional fragment thereof binds to
human IL-1.beta. with a dissociation constant of about 100 pM or
less. In some embodiments of any of the uses described above, the
IL-1.beta. binding antibody or functional fragment thereof binds to
human IL-1.beta. with a dissociation constant of about 5 pM or
less. In some embodiments, the IL-1.beta. binding antibody or
functional fragment thereof binds to human IL-1.beta. with a
dissociation constant of about 1 pM or less. In some embodiments,
the IL-1.beta. binding antibody or functional fragment thereof
binds to human IL-1.beta. with dissociation constant of about 0.3
pM or less.
[0113] In some embodiments of any of the uses described above, the
IL-1.beta. binding antibody or fragment thereof is a neutralizing
antibody.
[0114] The canakinumab heavy chain variable region (VH) is set
forth as SEQ ID NO:1 of the sequence listing. CDR1 of the VH of
canakinumab is set forth as SEQ ID NO:3 of the sequence listing.
CDR2 of the VH of canakinumab is set forth as SEQ ID NO:4 of the
sequence listing. CDR3 of the VH of canakinumab is set forth as SEQ
ID NO:5 of the sequence listing.
[0115] The canakinumab light chain variable region (VL) is set
forth as SEQ ID NO:2 of the sequence listing. CDR1 of the VL of
canakinumab is set forth as SEQ ID NO:6 of the sequence listing.
CDR2 of the VL of canakinumab is set forth as SEQ ID NO:7 of the
sequence listing. CDR3 of the VL of canakinumab is set forth as SEQ
ID NO:8 of the sequence listing.
[0116] In some embodiments of any of the uses described above, the
IL-1.beta. binding antibody or fragment thereof competes with the
binding of an antibody having the light chain variable region of
SEQ ID NO:1 and the heavy chain variable region of SEQ ID NO:2.
[0117] FIG. 7 illustrates the sequence of VH and of the three
CDRs.
[0118] In some embodiments, the disclosed uses, said IL-1.beta.
binding antibody having the three CDRs of SEQ ID NO:1. In further
embodiments, the three CDRs of SEQ ID NO:1 are set forth as SEQ ID
NOs:3-5. In some embodiments, the disclosed uses comprise
administering an anti-IL-1.beta. binding antibody having the three
CDRs of SEQ ID NO:2. In further embodiments, the three CDRs of SEQ
ID NO:2 are set forth as SEQ ID NOs:6-8.
[0119] FIG. 8 illustrates the sequence of VL and of the three
CDRs.
[0120] In some embodiments, the disclosed uses comprise
administering an anti-IL-1.beta. binding antibody having the three
CDRs of SEQ ID NO:1 and the three CDRs of SEQ ID NO:2. In further
embodiments, the three CDRs of SEQ ID NO:1 are set forth as SEQ ID
NOs:3-5 and the three CDRs of SEQ ID NO:2 are set forth as SEQ ID
NOs:6-8.
[0121] In some embodiments of any of the use described above, said
IL-1.beta. binding antibody or functional fragment thereof is to be
administered subcutaneously or intravenously.
[0122] When administered subcutaneously, canakinumab can be
administered in a reconstituted formulation comprising canakinumab
at concentration 10-150 mg/ml, 270 mM sucrose, 30 mM histidine and
0.06% polysorbate 80, wherein the pH of the formulation is 6.3-6.7,
preferably 6.5.
[0123] When administered subcutaneously, canakinumab can be
administered in a liquid formulation comprising canakinumab at
concentration: 10-150 mg/ml, 270 mM mannitol, 20 mM histidine and
0.04% polysorbate 80 (or polysorbate 20), wherein the pH of the
formulation is 6.3-6.7, preferably 6.5.
[0124] When administered subcutaneously, canakinumab or any of said
IL-1.beta. binding antibody or functional fragment thereof can be
administered to the patient in a liquid form or lyophilized form
for reconstitution contained in a prefilled syringe. In one
embodiment said prefilled syringe can be contained in an
autoinjector. Such autoinjector makes it possible for the patient
to selfadminister the liquid formulation subcutanously in an easy
manner.
[0125] In other embodiments according to any use of the invention,
patient reported outcomes which include tiredness, physical
function and performance function are assessed, and whereby said
patient reported outcomes (PRO) are improved.
[0126] In other embodiments of any use of the invention, said
patient is concomitantly receiving standard of care treatment for
preventing or reducing risk of experiencing recurrent CV events.
Said standard of care treatment is a lipid lowering agent such as a
HMG-CoA reductase inhibitor, e.g., a statin such as lovastatin,
pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin,
mevastatin, pitavastatin, rosuvastatin or mixtures thereof or
mixtures with ezetimibe, niacin, amlodipine besylate),
anti-hypertensives such as a calcium channel blocker (e.g.,
amlodipine, diltiazem, nifedipine, nicardipine, verapamil) or
beta-adrenergic blocking drugs such as esmolol, metoprolol,
nadolol, penbutolol or anti-hypertensives such as labetalol,
metoprolol, hydralazine, nitroglycerin, nicardipine, sodium
nitroprusside, clevidipine or a diuretic such as a thiazide
diuretic, chlorthalidone, furosemide, hydrochlorothiazide,
indapamide, metolazone, amiloride hydrochloride, spironolactone,
triamterene, or an angiotensin-converting enzyme (ACE) inhibitor
such as ramipril, ramiprilat, captopril, lisinopril or an
angiotensin II receptor blocker such as losartan, valsartan,
olmesartan, irbesartan, candesartan, telmisartan, eprosartan or an
anticoagulant such as acenocoumarol, coumatetralyl, dicoumarol,
ethyl biscoumacetate, phenprocoumon, warfarin heparin, low
molecular weight heparin such as bemiparin, certoparin, dalteparin,
enoxaparin, nadroparin, parnaparin, reviparin, tinzaparin or an
inhibitor of platelet aggregation such clopidogrel, elinogrel,
prasugrel, cangrelor, ticagrelor, ticlopidine, cilostazol,
dipyridamole, picodamide eptiftbatide, abciximab, eptifibatide,
tirofiban or terutroban or a Prostaglandin analogue (PGI2) such as
beraprost, prostacyclin, iloprost or treprostinil, or COX
inhibitors such as aspirin, aloxiprin or carbasalate calcium,
indobufen or triflusal or cloricromen or ditazole or
1,3-Indandiones such as clorindione, diphenadione or phenindion, or
tioclomarol, or direct thrombin (II) inhibitors such as hirudin,
bivalirudin, lepirudin, desirudin (bivalent) or argatroban or
dabigatran (monovalent) or oligosaccharides such as fondaparinux,
idraparinux, or an heparinoids such as danaparoid, sulodexide,
dermatan sulfate or direct Xa inhibitors xabans such as apixaban,
betrixaban, edoxaban, otamixaban, rivaroxaban or REG1 or
defibrotide or ramatroban or antithrombin III or protein C
(drotrecogin alfa) or fibrinolytics plasminogen activators: r-tPA
such as alteplase, reteplase, tenecteplase or UPA such as urokinase
or saruplase) or streptokinase or anistreplase or monteplase or
other serine endopeptidases or ancrod or fibrinolysin; or brinase
or citrate or EDTA or oxalate or digitalis, or digoxin, or
nesiritide, or oxygen, or a nitrate such as glyceryl trinitrate
(GTN)/nitroglycerin, isosorbide dinitrate, isosorbide mononitrate
or an analgesic such as morphine sulfate or a renin inhibitor such
as aliskiren or an endothelin A receptor inhibitor or an
aldosterone inhibitor.
[0127] In other embodiments of any use according to the invention,
biomarkers other than hsCRP include but are not limited to: IL-1Ra,
IL-6, IL-18, leptin, adiponectin (total and high MW), TNF.alpha.,
PAI-1 and fibrinogen.
[0128] Other embodiments of any aspect described above include a
pharmaceutical composition for preventing or reducing risk of
experiencing a recurrent cardiovascular (CV) event a
cerebrovascular event in a patient that has suffered of a
qualifying CV event, wherein about 25 mg to about 300 mg of an
IL-1.beta. binding antibody or functional fragment thereof is to be
administered, and wherein said patient has a CRP level of .gtoreq.
about 1 mg/L before administration of said antibody or functional
fragment thereof.
General:
[0129] All patents, published patent applications, publications,
references and other material referred to herein are incorporated
by reference herein in their entirety.
[0130] As used herein, the term "comprising" encompasses
"including" as well as "consisting," e.g. a composition
"comprising" X may consist exclusively of X or may include
something additional, e.g., X+Y.
[0131] As used herein, the term "administering" in relation to a
compound, e.g., an IL-1.beta. binding antibody or standard of care
agent, is used to refer to delivery of that compound by any route
of delivery.
[0132] As used herein, the term "assaying" is used to refer to the
act of detecting, identifying, screening, or determining, which act
may be performed by any conventional means. For example, a sample
may be assayed for the presence of a particular marker by using an
ELISA assay, a Northern blot, imaging, etc. to detect whether that
marker is present in the sample.
[0133] As used herein, The term "about" in relation to a numerical
value x means, for example, +/-10%.
[0134] As used herein, The word "substantially" does not exclude
"completely," e.g., a composition which is "substantially free"
from Y may be completely free from Y. Where necessary, the word
"substantially" may be omitted from the definition of the
disclosure.
[0135] As used herein, "C-reactive protein" and "CRP" refers to
serum C-reactive protein, which is used as an indicator of the
acute phase response to inflammation. The level of CRP in plasma
may be given in any concentration, e.g., mg/dl, mg/L, nmol/L.
Levels of CRP may be measured by a variety of well known methods,
e.g., radial immunodiffusion, electroimmunoassay,
immunoturbidimetry, ELISA, turbidimetric methods, fluorescence
polarization immunoassay, and laser nephelometry.
[0136] Testing for CRP may employ a standard CRP test or a high
sensitivity CRP (hsCRP) test (i.e., a high sensitivity test that is
capable of measuring low levels of CRP in a sample using laser
nephelometry). Kits for detecting levels of CRP may be purchased
from various companies, e.g., Calbiotech, Inc, Cayman Chemical,
Roche Diagnostics Corporation, Abazyme, DADE Behring, Abnova
Corporation, Aniara Corporation, Bio-Quant Inc., Siemens Healthcare
Diagnostics, etc.
[0137] As used herein, the term "hsCRP" refers to the level of CRP
in the blood as measured by high sensitivity CRP testing.
[0138] Each local laboratory will employ a cutoff value for
abnormal (high) CRP based on that laboratory's rule for calculating
normal maximum CRP. A physician generally orders a CRP test from a
local laboratory, and the local laboratory reports normal or
abnormal (low or high) CRP using the rule that particular
laboratory employs to calculate normal CRP.
[0139] By "IL-1.beta. binding antibody" is meant any antibody
capable of binding to the IL-1.beta. antigen either alone or
associated with other molecules. The binding reaction may be shown
by standard methods (qualitative assays) including, for example, a
bioassay for determining the inhibition of IL-1.beta. binding to
its receptor or any kind of binding assays, with reference to a
negative control test in which an antibody of unrelated specificity
but of the same isotype, e.g. an anti-CD25 antibody, is used.
Advantageously, the binding of the IL-1.beta. binding antibodies
used in the methods of the invention to IL-1.beta. may be shown in
a competitive binding assay.
[0140] As used herein the term "antibody" as referred to herein
includes whole antibodies and any antigen binding fragment or
single chains thereof (i.e., "functional fragment"). A naturally
occurring "antibody" is a glycoprotein comprising at least two
heavy (H) chains and two light (L) chains inter-connected by
disulfide bonds. Each heavy chain is comprised of a heavy chain
variable region (abbreviated herein as V.sub.H) and a heavy chain
constant region. The heavy chain constant region is comprised of
three domains, CH1, CH2 and CH3. Each light chain is comprised of a
light chain variable region (abbreviated herein as V.sub.L) and a
light chain constant region. The light chain constant region is
comprised of one domain, CL. The V.sub.H and V.sub.L regions can be
further subdivided into regions of hypervariability, termed
complementarity determining regions (CDR), interspersed with
regions that are more conserved, termed framework regions (FR).
Each V.sub.H and V.sub.L is composed of three CDRs and four FRs
arranged from amino-terminus to carboxy-terminus in the following
order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions
of the heavy and light chains contain a binding domain that
interacts with an antigen. The constant regions of the antibodies
may mediate the binding of the immunoglobulin to host tissues or
factors, including various cells of the immune system (e.g.,
effector cells) and the first component (Clq) of the classical
complement system.
[0141] As used herein, the term "functional fragment" of an
antibody as used herein, refers to portions or fragments of an
antibody that retain the ability to specifically bind to an antigen
(e.g., IL-1.beta.. It has been shown that the antigen-binding
function of an antibody can be performed by fragments of a
full-length antibody. Examples of binding fragments encompassed
within the term "functional fragment" of an antibody include a Fab
fragment, a monovalent fragment consisting of the V.sub.L, V.sub.H,
CL and CH1 domains; a F(ab).sub.2 fragment, a bivalent fragment
comprising two Fab fragments linked by a disulfide bridge at the
hinge region; a Fd fragment consisting of the V.sub.H and CH1
domains; a Fv fragment consisting of the V.sub.L and V.sub.H
domains of a single arm of an antibody; a dAb fragment (Ward et
al., 1989), which consists of a V.sub.H domain; and an isolated
complementarity determining region (CDR). Exemplary antigen binding
sites include the CDRs of canakinumab as set forth in SEQ ID NOs:
3-5 and SEQ ID NOs: 6-8. Although the two domains of the Fv
fragment, V.sub.L and V.sub.H, are coded for by separate genes,
they can be joined, using recombinant methods, by a synthetic
linker that enables them to be made as a single protein chain in
which the V.sub.L and V.sub.H regions pair to form monovalent
molecules (known as single chain Fv (scFv); see, e.g., Bird et al.,
1988; and Huston et al., 1988). Such single chain antibodies are
also intended to be encompassed within the term "functional
fragments" of an antibody. These antibody fragments are obtained
using conventional techniques known to those of skill in the art,
and the fragments are screened for utility in the same manner as
are intact antibodies.
[0142] As used herein, the terms "monoclonal antibody" or
"monoclonal antibody composition" as used herein refer to a
preparation of antibody molecules of single molecular composition.
A monoclonal antibody composition displays a single binding
specificity and affinity for a particular epitope.
[0143] As used herein, the term "human antibody", as used herein,
is intended to include antibodies having variable regions in which
both the framework and CDR regions are derived from sequences of
human origin. Furthermore, if the antibody contains a constant
region, the constant region also is derived from such human
sequences, e.g., human germline sequences, or mutated versions of
human germline sequences or antibody containing consensus framework
sequences derived from human framework sequences analysis as
described in Knappik, et al. A "human antibody" need not be
produced by a human, human tissue or human cell. The human
antibodies of the disclosure may include amino acid residues not
encoded by human sequences (e.g., mutations introduced by random or
site-specific mutagenesis in vitro or by somatic mutation in vivo).
However, the term "human antibody", as used herein, is not intended
to include antibodies in which CDR sequences derived from the
germline of another mammalian species, such as a mouse, have been
grafted onto human framework sequences.
[0144] As used herein, the term "K.sub.D", as used herein, is
intended to refer to the dissociation constant, which is obtained
from the ratio of K.sub.d to K.sub.a (i.e. K.sub.d/K.sub.a) and is
expressed as a molar concentration (M). K.sub.D values for
antibodies can be determined using methods well established in the
art. A method for determining the K.sub.D of an antibody is by
using surface plasmon resonance, or using a biosensor system such
as a Biacore.RTM. system.
[0145] As used herein, the term "patient" includes any human or
nonhuman animal. The term "nonhuman animal" includes all
vertebrates, e.g., mammals and non-mammals, such as nonhuman
primates, sheep, dogs, cats, horses, cows, chickens, amphibians,
reptiles, etc.
[0146] As used herein, an antibody that "inhibits" one or more of
these IL-1.beta. functional properties (e.g., biochemical,
immunochemical, cellular, physiological or other biological
activities, or the like) as determined according to methodologies
known to the art and described herein, will be understood to relate
to a statistically significant decrease in the particular activity
relative to that seen in the absence of the antibody (or when a
control antibody of irrelevant specificity is present). An antibody
that inhibits IL-1.beta. activity affects a statistically
significant decrease, e.g., by at least 10% of the measured
parameter, by at least 50%, 80% or 90%, and in certain embodiments
an antibody of the disclosure may inhibit greater than 95%, 98% or
99% of IL-17 functional activity.
[0147] As used herein the term "polypeptide", if not otherwise
specified herein, includes any peptide or protein comprising amino
acids joined to each other by peptide bonds, having an amino acid
sequence starting at the N-terminal extremity and ending at the
C-terminal extremity.
[0148] As used herein, the term "qualifying CV event" is MI,
stroke, unstable angina, revascularization, stent thrombosis, acute
coronary syndrome or any other CV event (excluding cardiovascular
death) which precedes the start of IL-1.beta. binding antibody or
functional fragment thereof therapy. In particular MI is a
preferred qualifying CV event.
[0149] As used herein, the term "recurrent CV event" is a repeated
CV event including but not limited to CV death, MI, or acute
coronary syndrome which takes place after said qualifying CV
event.
[0150] As used herein "cerebrovascular disease" is a group of brain
dysfunctions related to disease of the blood vessels supplying the
brain. This definition includes but are not limited to stroke.
[0151] As used herein, the term "cardiovascular death" includes
sudden cardiac death, death due to acute myocardial infarction,
death due to heart failure, death due to stroke, and death due to
other cardiovascular causes.
[0152] As used herein, "sudden cardiac death" is a sudden death
that occurs in a previously stable patient who does not have a
prior terminal condition, such as malignancy not in remission or
end-stage chronic lung disease.
[0153] Death due to acute myocardial infarction (AMI): refers to a
death within 30 days after a myocardial infarction (MI) related to
consequences seen immediately after the myocardial infarction, such
as progressive congestive heart failure (CHF), inadequate cardiac
output, or recalcitrant arrhythmia. If these events occur after a
"break" (e.g., a CHF and arrhythmia free period), they should be
designated by the immediate cause. The acute myocardial infarction
should be verified either by the diagnostic criteria outlined for
acute myocardial infarction or by autopsy findings showing recent
myocardial infarction or recent coronary thrombus, and there should
be no conclusive evidence of another cause of death.
[0154] Sudden, unexpected cardiac death, involving cardiac arrest,
often with symptoms suggestive of myocardial ischemia, and
accompanied by presumably new ST elevation, or new LBBB and/or
evidence of fresh thrombus by coronary angiography and/or at
autopsy, but death occurring before blood samples could be
obtained, or at a time before the appearance of cardiac biomarkers
in the blood should be considered death due to acute myocardial
infarction.
[0155] If death occurs before biochemical confirmation of
myocardial necrosis can be obtained, adjudication should be based
on clinical presentation and ECG evidence.
[0156] Death resulting from a procedure to treat myocardial
ischemia or to treat a complication resulting from myocardial
infarction should also be considered death due to acute MI.
[0157] Death due to a myocardial infarction that occurs as a direct
consequence of a cardiovascular investigation/procedure/operation
should be classified as death due to other cardiovascular
cause.
[0158] Death due to heart failure or cardiogenic shock refers to
death occurring in the context of clinically worsening symptoms
and/or signs of heart without evidence of another cause of
death.
[0159] Death due to heart failure or cardiogenic shock should
include sudden death occurring during an admission for worsening
heart failure as well as death from progressive heart failure or
cardiogenic shock following implantation of a mechanical assist
device.
[0160] Death due to stroke (intracranial hemorrhage or
non-hemorrhagic stroke) refers to death occurring up to 30 days
after a suspected stroke based on clinical signs and symptoms as
well as neuroimaging and/or autopsy, and where there is no
conclusive evidence of another cause of death.
[0161] As used herein, "death due to other cardiovascular causes"
refers to death due to a cardiovascular cause not included in the
above categories (e.g. dysrhythmia, pulmonary embolism,
cardiovascular intervention, aortic aneurysm rupture, or peripheral
arterial disease). Mortal complications of cardiac surgery or
non-surgical revascularization, even if "non-cardiovascular" in
nature, should be classified as cardiovascular deaths.
[0162] As used herein the term "death of undetermined cause"
(presumed cardiovascular) refers to all deaths not attributed to
the categories of cardiovascular Death or to a non-cardiovascular
cause are considered presumed cardiovascular deaths. As used
herein, "non-cardiovascular death" is defined as any death not
covered by cardiac death or vascular death and is categorized as
follows: pulmonary causes, renal causes, gastrointestinal causes,
infection (including sepsis), non-infectious causes, malignancy,
accident/Trauma, suicide, non-cardiovascular system organ failure
(e.g. hepatic), hemorrhage, not intracranial or other.
[0163] As used herein, the term "myocardial infarction (MI)" refers
to "acute Myocardial Infarction": the term myocardial infarction
(MI) should be used when there is evidence of myocardial necrosis
in a clinical setting consistent with myocardial ischemia. Under
these conditions any one of the following criteria meets the
diagnosis for MI.
[0164] The term "spontaneous MI" refers to the detection of rise
and/or fall of cardiac biomarkers with at least one value above the
99.sup.th percentile of the upper reference limit (URL) together
with evidence of myocardial ischemia with at least one of the
following: symptoms of ischemia, ECG changes indicative of new
ischemia), development of pathological Q waves in the ECG, imaging
evidence of new loss of viable myocardium or new regional wall
motion abnormality.
[0165] The term "percutaneous coronary intervention (PCI) related
myocardial infarct" refers to PCI in patients with normal baseline
troponin values elevations of cardiac biomarkers above the
99.sup.th percentile URL within 24 hours of the procedure are
indicative of peri-procedural myocardial necrosis. By convention
increases of biomarkers greater than 3.times.99.sup.th percentile
URL are consistent with PCI related myocardial infarction. If the
cardiac biomarker is elevated prior to PCI a .gtoreq.20% increase
of the value in that second cardiac biomarker within 24 hours of
the PCI and documentation that cardiac biomarkers were decreasing
(two samples at least 6 hours apart) prior to the suspected
recurrent MI is also consistent with PCI related MI. Symptoms of
cardiac ischemia are not required
[0166] The term "CABG related myocardial infarct" refers to CABG in
patients with normal baseline troponin, elevations of cardiac
biomarkers above 5 times the 99.sup.th percentile of the normal
reference range during the first 72 hours after CABG, when
associated with either new pathological Q waves in at least 2
contiguous leads on the ECG that persist through 30 days or new
left bundle branch block (LBBB) or angiographically documented new
graft or native coronary artery occlusion or imaging evidence of
new loss of viable myocardium
[0167] If the cardiac biomarker is elevated prior to CABG a
.gtoreq.20% increase of the value in the second cardiac biomarker
within 72 hours of CABG AND documentation that the cardiac
biomarkers were decreasing (2 samples at least 6 hours apart) prior
to the suspected recurrent MI plus either new pathological Q waves
in at least 2 contiguous leads on the ECG or new LBBB,
angiographically documented new graft or native artery occlusion or
imaging evidence or new loss of viable myocardium is consistent
with a peri-procedural myocardial infarct after CABG. Symptoms of
cardiac ischemia are not required.
[0168] Criteria for Prior Myocardial Infarction: Any of the
following criteria meets the diagnosis for prior myocardial
infarction: development of new pathological Q waves with or without
symptoms, imaging evidence of a region of loss of viable myocardium
that is thinned and fails to contract in the absence of a
non-ischemic cause, pathological findings of a healed or healing
myocardial infarction
[0169] ECG changes associated with prior Myocardial Infarction:
[0170] Any Q wave in leads V2-V3.gtoreq.0.02 seconds or QS complex
in leads V2 and V3 [0171] Q-wave .gtoreq.0.03 seconds and
.gtoreq.0.1 mV deep or QS complex in leads I, II, aVL, aVF, or
V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V6,
V4-V6, II, III, and aVF) [0172] R-wave .gtoreq.0.04 seconds in
V1-V2 and R/S.gtoreq.1 with a concordant positive T-wave in the
absence of a conduction defect
[0173] Criterion for Reinfarction: In patients where recurrent MI
is suspected from clinical signs or symptoms following the initial
infarction, an immediate measurement of the employed cardiac
biomarker is recommended. A second sample should be obtained 3-6
hours later. Recurrent infarction is diagnosed if there is a
.gtoreq.20% increase of the value in the second sample. This value
should exceed the 99.sup.th percentile URL. However if cardiac
biomarkers are elevated prior to the suspected new MI, there must
also be documentation of decreasing values (two samples at least 6
hours apart) prior to the suspected new MI. If the values are
falling criteria for reinfarction by further measurement of
biomarkers together with features of the ECG or imaging can be
applied.
[0174] ECG diagnosis of reinfarction following the initial
infarction: may be confounded by the initial evolutionary ECG
changes. Reinfarction should be considered when the ST elevation
.gtoreq.0.1 mV reoccurs in an inpatient having a lesser degree of
ST elevation or new pathognomonic Q-waves, in at least two
contiguous leads, particularly when associated with ischemic
symptoms for 10 minutes or longer, The re-evaluation of the ST
segment can, however also be seen in threatening myocardial rupture
and should lead to additional diagnostic work-up. ST depression or
LBBB on their own should not be considered valid criteria for
Myocardial Infarction.
[0175] If biomarkers are increasing or peak is not reached then
there is insufficient data to diagnose recurrent MI.
[0176] Clinical Classification of different types of Myocardial
Infarction: for each MI identified a Type of MI will be assigned
using the following guidelines: [0177] Type 1--Spontaneous MI
related to ischemia due to a primary coronary event such as plaque
erosion and/or rupture, fissuring or dissection. [0178] Type 2--MI
secondary to ischemia due to either increased oxygen demand or
decreased supply, e.g. coronary artery spasm, anemia, hypotension,
coronary embolism, arrhythmias, hypertension or hypotension. [0179]
Type 3--Sudden unexpected cardiac death including cardiac arrest,
often with symptoms suggestive of myocardial ischemia accompanied
by presumably new ST elevation, or new LBBB, or evidence of fresh
thrombus in a coronary artery by angiography and/or at autopsy, but
death occurring before blood samples could be obtained or at a time
before the appearance of cardiac biomarkers in the blood. [0180]
Type 4a--MI associated with PCI. [0181] Type 4b--MI associated with
stent thrombosis as documented by autopsy or angiography. [0182]
Type 5--MI associated with CABG.
[0183] The term "silent MI": the following criteria will be used by
the central ECG reading vendor to define interval "silent" (no
clinical symptoms or signs) MI between baseline and yearly
ECGs:
[0184] Criteria for MI (Surawcz, Ed: Chou's Electrocardiography in
Clinical Practice, 5th Edition, 2001).
[0185] Myocardial infarctions are reported only on the basis of
pathologic Q waves. Pathologic Q waves are defined as Q wave
duration .gtoreq.40 ms and Q/R ratio=1/3.
[0186] Any Q wave in V1 or V2 that is followed by an R wave should
be considered abnormal.
[0187] When pathologic Q waves (i.e., myocardial infarction) are
present, ST elevation or T wave inversion may be used to classify
the infraction as New or Acute. However, ST elevation or T wave
inversion in the absence of pathologic Q waves are not sufficient
criteria for diagnosis of myocardial infarction. [0188]
Anterolateral MI--Pathologic Q waves in leads V3-V6. [0189]
Anterior MI--Pathologic Q waves in V3 and V4. [0190] Anteroseptal
MI--Pathologic Q waves or QS in leads V1-V4. [0191] Extensive
Anterior MI--Pathologic Q waves in leads I, aVL, and V1-V6. [0192]
High lateral MI--Pathologic Q waves in leads I and aVL. [0193]
Inferior MI--Pathologic Q waves or QS in at least two of the
inferior leads: aVF, III, II. [0194] Lateral MI--Pathologic Q waves
in leads I, aVL, and V5-V6. [0195] Septal MI--Pathologic Q waves or
QS in leads V1-V2, (V3). In the presence of LAHB or LVH a Q or QS
in V3 is required. [0196] Posterior MI--Initial R wave duration 40
ms in V1 or V2, and R>S and upright T wave; Inferior or Lateral
MI are usually also present.
[0197] The term "new MI" These criteria for MI are more stringent
than the Expert Consensus Document criteria, requiring Q waves to
be .gtoreq.0.04 sec in duration and an R/S ratio.gtoreq.1/3. These
criteria (drawn from the cardiology literature) are designed to
minimize the false positive detection of MIs due to very small
physiologic Q waves in the inferior and anterolateral leads.
[0198] As used herein, the term "stroke" is defined as the rapid
onset of a new persistent neurological deficit attributed to an
obstruction in cerebral blood flow and/or cerebral hemorrhage with
no apparent non-vascular cause (e.g. tumor, trauma, infection).
Available neuroimaging studies will be considered to support the
clinical impression and to determine if there is a demonstrable
lesion compatible with an acute stroke. Non-fatal strokes will be
classified as ischemic, hemorrhagic or unknown.
[0199] As used herein the term "stent thrombosis" is defined as
follows:
TABLE-US-00001 Type Timing Acute stent thrombosis* 0 to 24 hours
after stent implantation Subacute stent thrombosis > 24 hours to
30 days after stent implantation Late stent thrombosis.dagger. >
30 days to 1 year after stent implantatin Very late stent
thrombosis.dagger. > 1 year after stent implantation Stent
thrombosis should be reported as a cumulative value over time and
at the various individual time points specified above. Time 0 is
defined as the time point after the guiding catheter has been
removed and the patient has left the catheterization laboratory.
*Acute or subacute can also be replaced by the term early stent
thrombosis. Early stent thrombosis (0 to 30 days) will be used in
the remainder of this document. .dagger.Includes primary as well as
secondary late stent thrombosis: secondary late stent thrombosis is
a stent thrombosis after a target lesion revascularization.
[0200] "Definite stent thrombosis" refers to a stent thormbosis
considered to have occurred by either angiographic or pathological
confirmation.
[0201] Angiographic confirmation of stent thrombosis:
[0202] The presence of a thrombus that originates in the stent or
in the segment 5 mm proximal or distal to the stent and presence of
at least 1 of the following within a 48 hour time window: acute
onset of ischemic symptoms at rest, new ischemic ECG changes that
suggest acute ischemia, typical rise and fall in cardiac
biomarkers, non-occlusive thrombus, occlusive thrombus.
Pathological Confirmation of Stent Thrombosis.:
[0203] Evidence of recent thrombosis within the stent determined at
autopsy or via examination of tissue retrieved following
thrombectomy.
[0204] The term "probable stent thrombosis" refers to stent
stenosis which is considered to have occurred after intracoronary
stenting in the following cases: any unexplained death within the
first 30 day, or irrespective of the time after the index
procedure, any MI that is related to documented acute ischemia in
the territory of the implanted stent without angiographic
confirmation of stent thrombosis and in the absence of any other
cause.
[0205] As used herein the term "unstable angina requiring unplanned
revascularization" is defined as no elevation in cardiac biomarkers
and clinical presentation (one of the following) with cardiac
symptoms lasting .gtoreq.10 minutes and considered to be myocardial
ischemia on final diagnosis (rest angina or new onset (<2
months) severe angina (CCS classification severity .gtoreq.III;
Grading of Angina Pectoris According to Canadian Cardiovascular
Society Classification) or increasing angina (in intensity,
duration and/or frequency) and severe recurrent ischemia requiring
urgent revascularization: as defined by an episode of angina
prompting the performance of coronary revascularization on the
index hospitalization or an episode of recurrent angina after
discharge that resulted in re-hospitalization during which coronary
revascularization was performed; and at least one of the following:
new or worsening ST or T segment changes on ECG, ST Elevation (new
ST elevation at the J point in two anatomically contiguous leads
with the cut-off points: .gtoreq.0.2 mV in men (>0.25 mV in men
<40 years) or .gtoreq.0.15 mV in women in leads V2-V3 and/or
.gtoreq.0.1 mV in other leads), ST depression and T-wave Evidence
of ischemia on stress testing with cardiac imaging, evidence of
ischemia on stress testing without cardiac imaging but with
angiographic evidence of .gtoreq.70% lesion, and/or thrombus in the
epicardial coronary artery or initiation/increased dosing of
anti-anginal therapy, angiographic evidence of .gtoreq.70% lesion
and/or thrombus in an epicardial coronary artery.
[0206] As used herein, the term "heart failure requiring
hospitalization" is defined as an event that meets the following
criteria:
[0207] Requires hospitalization defined as an admission to an
inpatient unit or a visit to an emergency department that results
in at least a 12 hour stay (or a date change if the time of
admission/discharge is not available) AND clinical manifestation of
heart failure including at least one of the following: New or
worsening: dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema,
pulmonary basilar crackles, radiological evidence of worsening
heart failure AND additional/increased therapy (initiation of IV
loop diuretic, inotrope or vasodilator therapy, uptitration of IV
therapy; if already on therapy initiation of mechanical or surgical
intervention, or use of ultra-filtration, hemofiltration or
dialysis that is specifically directed at the treatment of heart
failure).
[0208] Biomarker results (e.g. brain natriuretic peptide)
consistent with congestive heart failure will be supportive of this
diagnosis.
[0209] As used herein, the term "prediabetes" is defined as the
state in which some but not all of the diagnostic criteria for
diabetes are met. It is often described as the "gray area" between
normal blood sugar and diabetic levels. While in this range,
patients are at risk for not only developing type 2 diabetes, but
also for cardiovascular complications. Prediabetes is also referred
to as borderline diabetes, impaired glucose tolerance (IGT), and/or
impaired fasting glucose (IFG).
[0210] As used herein the term "new onset diabetes" (NOD) refers
to:
[0211] The clinical definition of Type 2 diabetes consists of the
following
[0212] Presence of Fasting Plasma Glucose measured on two
consecutive occasions .gtoreq.126 mg/dl within 6 weeks (the Event
Date will be the first of these two occasions), or
presence of HbAlc measured on two consecutive occasions
.gtoreq.6.5% within 6 weeks in a laboratory which has validated
compliance of a test that conforms to the National Glycosylation
Standards Program (Little et al 2010) reference measurement of
HbAlc (the Event Date will be the first of these two occasions), or
the institution and use of a diabetes medication for the purpose of
glucose control by the patient including all oral agents, insulin,
and injectable GLP-1 analogs.
[0213] In the event wherein a patient has one laboratory parameter
which would place them in the NOD category if repeated and
confirmed within 6 weeks, then has a subsequent measurement another
parameter which similarly would place them in the NOD category if
repeated and confirmed within 6 weeks (e.g. FPG.gtoreq.126 mg/dl
followed by HbAlc.gtoreq.6.5%, or vice versa) will be considered to
have NOD (the Event Date will be the first of these 2
occasions).
[0214] As used herein the term "transient ischemic attack" is
defined as change in the blood supply to a particular area of the
brain, spinal cord, or retina, resulting in brief neurologic
dysfunction that persists, by definition, for less than 24
hours.
[0215] New and focal neurologic sensory and/or motor deficits,
which have a rapid onset, last no more than 24 hours and resolve
completely. Symptoms may be localized to brain, spinal cord, or
retina, relative to the vascular supply affecting neurologic
function.
[0216] Focal sensory, reflexes, and motor lesions, which are
manifestations of the arterial structure from which the
insufficiency arises. All new neurologic signs resolve completely
within 24 hours from the time of onset (hemiplegia/paresis,
hemianaesthesia/sensory deficit, hemianopsia, neglect, isolated
facial weakness/droop, ataxia/dysmetria, dysarthria/speech
impairment, aphasia or other.
[0217] A CT, MRI, or MRA of the brain, which demonstrates no new
pathology. A neurological or neurosurgical consultation may
accompany the imaging study or studies, but is not required for the
diagnosis of TIA.
[0218] As used herein the term "critical limb ischemia" is a
manifestation of occlusive peripheral arterial disease that
describes patients with chronic occlusive disease who demonstrate
ischemic rest pain or ischemic skin lesions (either ulcers or
gangrene).
[0219] Pain at rest, claudication, recurrent skin lesions are
common Coolness to touch and pallor of the involved extremity may
be present. Diminution or absence of pulse to palpation or bedside
Doppler examination. Ulcers of the skin may be present.
[0220] CT, MRI, MRA or angiography may be performed for diagnostic
purposes. Angiographic or open revascularization may be attempted
to improve arterial blood flow.
[0221] The term "limb amputation due to vascular cause" refers to
therapeutic resection of a limb or a portion of a limb due to a
combination of vascular insufficiency, osteomyelitis,
cellulitis/gangrene, or poor wound healing.
[0222] Symptoms may include claudication, rest pain, fever, and
recurrent infections. There may be a history of previous partial or
complete amputations.
[0223] Signs may include decreased arterial pulse, abnormal
temperature, deformity, chronic skin ulceration.
[0224] Therapeutic resection of the pathologic extremity: Reasons
for amputation may be vascular insufficiency, osteomyelitis,
cellulitis, gangrene, poor healing post-surgical wound, poor
healing post trauma.
[0225] As used herein the term "non-coronary revascularization" is
defined as vascular surgery or percutaneous intervention. Vascular
surgery is defined as the placement of a conduit with or without
proximal and/or distal anastamoses. Percutaneous intervention is
defined as balloon inflation with or without stenting.
[0226] Symptoms will be specific to the arterial vasculature
involved and the time of course of development of the
occlusion(s).
[0227] Signs will be specific to the arterial vasculature involved
and the time of course of development of the occlusion(s).
[0228] Diagnostic CT, MRI, MRA, or Doppler US may be performed.
[0229] Revascularization or attempted revascularization with or
without stenting including carotid surgery, peripheral vascular
surgery or PCI, including abdominal aortic aneurysm repair, carotid
revascularization, femoral, popliteal iliac, renal, open or
percutaneous peripheral interventions depending on the site
definition of supraventricular tachycardia/atrial fibrillation
[0230] Supraventricular tachycardia includes abnormal sinus
tachycardia, ectopic atrial tachycardia atrial fibrillation/atrial
flutter (with rapid ventricular response) and junctional
tachycardia.
[0231] As used herein "deep vein thrombosis" (DVT) is defined as
the pathologic presence of thrombus with inflammation, which
affects the leg veins (such as the femoral vein or the popliteal
vein), the deep veins of the pelvis, or rarely an upper extremity
vein.
[0232] There may be no symptoms referable to the location of the
DVT, but the classical symptoms of DVT include pain, swelling and
redness of the leg and dilation of the surface veins
[0233] DVT include pain, swelling and redness of the leg and
dilation of the surface veins may be present. Homan's sign,
posterior calf pain on foot dorsiflexion may be present but is an
insensitive indicator. Commonly, no signs are present.
[0234] Duplex ultrasonography is the most commonly used diagnostic
test. Other tests may include d-dimer blood testing, CT with
contrast, and infrequently venography. Confirmation by diagnostic
study required.
[0235] As used herein, a "pulmonary embolism" is defined as an
acute blockage of one or more pulmonary arteries by an embolus,
which has originated elsewhere (usually venous thrombus) and
traveled through the venous system to reach the pulmonary
arteries.
[0236] Symptoms may include sudden-onset dyspnea, tachypnea, chest
pleuritic chest pain, cough, and hemoptysis. In addition, severe
cases can include signs such as cyanosis, tachycardia, hypotension,
and syncope.
[0237] Chest X-Rays may be performed but are rarely diagnostic.
Blood testing for d-dimer is often used to screen prior to
performing medical imaging. Spiral CT of the chest is often
performed. If significant pathology makes spiral CT less useful, a
ventilation perfusion scan of the chest may be available.
Confirmation by diagnostic study and localization (left or right
lung and lobe) required.
[0238] A used herein "coronary angiography" is an invasive
procedure wherein radiocontrast dye is introduced via an arterial
catheter into the aorta, left ventricle, and coronary arteries to
examine the functional capacity and anatomy of these entities.
[0239] A radiocontrast dye is administered as described above by a
cardiologist or invasive radiologist, using peripheral access into
an artery (femoral or brachial).
[0240] As used herein "coronary revascularization" is defined as an
invasive procedure, which usually follows coronary angiography,
wherein either percutaneous transluminal intervention, followed by
Stent Placement, Balloon Angioplasty, or CABG is performed to
relieve obstructed coronary arteries. A team of medical
professionals lead by either an invasive cardiologist (percutaneous
transluminal intervention, followed by stent placement, balloon
angioplasty,) or a thoracic surgeon (CABG), who performs the
described procedures.
[0241] As used herein, supraventricular tachycardia (SVT)/atrial
fibrillation includes abnormal sinus tachycardia, ectopic atrial
tachycardia atrial fibrillation/atrial flutter (with rapid
ventricular response) and junctional tachycardia.
[0242] Symptoms may include palpitations, dyspnea, chest pain,
dizziness, numbness or loss of consciousness. Signs may include
rapid heart rate, which may be regular or irregular. Peripheral
pulses may be diminished or absent.
[0243] ECG demonstrates narrow complex tachycardia originating from
a site (or sites) above the ventricles. P waves may or may not be
present, depending on the specific type of SVT.
[0244] Patient Reported Outcome Measures: EQ-5D
[0245] Generic multidimensional health-related quality of life will
be assessed with the EuroQoL (EQ-5D). The EuroQol EQ-5D is a simple
but effective standardized instrument designed for use as a measure
of health outcome. Applicable to a wide range of health conditions
and treatments, it provides both a compact descriptive profile and
a single index value that can be used in the clinical and economic
evaluation of health care.
[0246] The EQ-5D measures five domains (mobility, self-care, usual
activity, pain/discomfort & anxiety/depression). There are two
parts to this questionnaire.
[0247] The first, `health state classification` consists of five
questions.
[0248] The second, `Visual Analogue Scale Thermometer` consists of
a visual analogue scale.
[0249] This generates a self-rating of current health-related
quality of life. This will be used with the health state
classification to build a composite picture of the respondent's
health status.
Data Capture:
[0250] EQ-5D enables an accurate self-description of current
health-related quality of life to be easily recorded.
Self-explanatory instructions to respondents are provided within
the questionnaire and it takes about two minutes to complete.
[0251] Health State Classification: The first page consists of five
questions. The respondent is asked to indicate his/her current
health state, by ticking the most appropriate of three statements
about each of the five quality of life dimensions. Each statement
represents an increasing level of severity (1=no problem, 2=some or
moderate problem, 3=unable or extreme problem). For example, a
respondent with `no problem` for each of the five questions will be
said to have a health status of 11111.
[0252] Visual Analogue Scale `Thermometer`: The `Thermometer` has
end points of 100 (best imaginable health state) at the top and 0
(worst imaginable health status) at the bottom. The respondent will
rate his/her current health status by drawing a line from the box
marked `Your health status today` to the appropriate point on the
`thermometer` scale.
[0253] The site staff should record the two digits reading on the
thermometer (where the line by the respondent crosses the
thermometer) on the appropriate space in the CRF. Missing or
ambiguous values will be left blank.
Example 1
A Randomized, Double-Blind, Placebo-Controlled, Event-Driven Trial
of Quarterly Subcutaneous Canakinumab in the Prevention of
Recurrent Cardiovascular Events Among Stable Post-Myocardial
Infarction Patients with Elevated hsCRP
[0254] This study is a Phase 3, multi-center, randomized, parallel
group, placebo-controlled, double-blind event-driven clinical
trial.
[0255] Screening will take place no earlier than: [0256] 28 days
after the index MI and on stable long term medication. [0257] 28
days after a PCI if it was during a different hospital admission
than the qualifying MI. Screening can only be initiated following
this procedure. [0258] 3 years post a CABG procedure regardless of
timing of the qualifying MI.
Rationale of Study Design
[0259] This study has been designed as a multi-center, randomized,
parallel group, placebo-controlled, double-blind, event-driven
trial to provide definitive evidence on the effects of canakinumab
on cardiovascular adverse events in patients with recent MI and
elevated inflammatory burden as evidenced by elevated hsCRP. This
study will also measure the effects of canakinumab on the
conversion to NOD as a secondary endpoint. This study design is the
most robust clinical trial design to test the hypothesis that
anti-inflammatory treatment with canakinumab will reduce major
adverse cardiovascular events.
Rationale of Dose/Regimen, Duration of Treatment
[0260] Canakinumab in doses starting from 25 mg to 300 mg with
increments of 5 mg will be used to select the optimal dose
regarding to the risk-benefit ratio for various subgroups of
post-myocardial infarction patients e.g. elderly patients when
necessary. Further, this dosing interval facilitates adjustment of
doses for factors influencing pharmacokinetic parameters e.g. body
weight to maintain blood concentrations of canakinumab at optimal
level when necessary.
Canakinumab 50 mg and 150 mg Quarterly
[0261] The 50 mg and 150 mg canakinumab dosing schedule has been
selected on the basis of anticipated efficacy, safety, and
biomarker modeling data. In phase II development, all canakinumab
doses up to 300 mg subcutaneous (s.c.) every other week have been
found safe, well tolerated, and free of adverse lipid effects.
Canakinumab efficacy in lowering hsCRP, IL-6 and fibrinogen was
assessed based on studies CACZ885A2213 and CACZ88512202. The
maximum efficacy of hsCRP lowering in study CACZ88512202 was at
approximately 50-75 mg of canakinumab monthly, with persistent
lowering across a wide range of higher doses. Therefore, 50 mg
monthly as fully efficacious dose and 15 mg monthly as submaximal
dose were selected for further development (see FIG. 6). The
optimal dosing interval was examined using data from CACZ885A2213
(diabetes) and from gout studies with canakinumab (see FIG. 4).
These studies indicated that canakinumab effect on lowering hsCRP
was durable for up to approximately 3 months (see FIG. 3). Further,
modeling and simulation methods showed that 150 mg quarterly dosing
had similar free IL-1.beta. suppression compared to 50 mg monthly
dosing and 50 mg quarterly dosing had similar free IL-1.beta.
suppression compared to 15 mg monthly dosing. This conclusion was
reached by comparing the doses and regimens based on both the time
for maintenance of suppression and the fraction of patients below a
specified suppression threshold of `tissue free` IL-1.beta..
Therefore, canakinumab 50 mg and 150 mg quarterly administration
were selected for the doses in this study, CACZ885M2301. The
selected doses allow examination canakinumab dose response in
preventing recurrent cardiovascular events and to determine if a
lower dose than 150 mg would have a favorable risk benefit
ratio.
Canakinumab 300 mg Quarterly
[0262] Given evidence of safety across a wide dosing range, a 300
mg quarterly dosing schedule for canakinumab has also been
developed for CACZ885M2301. This allows evaluation of a higher
canakinumab dose since the dose needed for adequate IL-1.beta.
neutralization within the plaque or systemically in
inflammation-based atherosclerosis is not established. Therefore, a
higher dose may deliver greater efficacy than the other selected
dose, 150 mg quarterly. This 300 mg quarterly dosing regimen also
includes an induction period over 2 weeks, dosing at randomization
(month 0) and at week 2 (month 0.5), in order to assure that
auto-induction of IL-1.beta. pathway is adequately inhibited at
study initiation. The complete suppression of IL-1.beta. related
gene expression achieved with this early high dose administration,
coupled with the continuous canakinumab treatment effect which has
been proven to last the entire quarterly dosing period, is expected
to minimize the potential for IL-1.beta. rebound. This may be
relevant for pathogenesis of atherosclerosis because it is
theorized that IL-1 auto-induction provides a positive feedback
mechanism for vascular disease including atherosclerosis. The lower
50 mg and 150 mg quarterly doses does not include an early high,
induction dose regimen to ensure separation of the three
canakinumab dose levels included in this protocol and to allow
assessment of the impact of the early high dose regimen included in
the 300 mg arm on clinical cardiovascular events.
[0263] In phase II studies in patients with gout, diabetes, and
acute inflammatory conditions, safety of canakinumab across a wide
range of doses has not emerged as a major clinical issue. Due to
long term suppression of inflammatory biomarkers, quarterly dosing
of canakinumab is feasible and likely to be clinically effective.
In addition, data in the setting of acute inflammation suggests
that higher initial doses of canakinumab that can be achieved
through induction are safe and provide an opportunity to ameliorate
concern regarding potential auto-induction of IL-1.beta. and to
achieve greater early suppression of IL-1.beta. related gene
expression. IL-1.beta. auto-induction has been shown in human
mononuclear blood, human vascular endothelial, and vascular smooth
muscle cells in vitro and in rabbits in vivo where IL-1 has been
shown to induce its own gene expression and circulating IL-1.beta.
level (Dinarello et al. 1987, Warner et al. 1987a, and Warner et
al. 1987b). These studies suggested that IL-1 induced IL-1 gene
expression may provide a positive feedback mechanism in the
pathogenesis of atherosclerosis and promote atherosclerosis. This
consequently suggests that suppression of this feedback mechanism
may provide benefits in the atherosclerotic lesion. Specifically,
data supporting an induction dose of canakinumab includes the
following: In CACZ885A2102, a CAPS mechanism of action study of
patients with Muckle Wells Syndrome (N=4), canakinumab treatment
with 10 mg/kg i.v. (equivalent to 600 mg i.v.) single dose induced
clinical (improved skin lesions and conjuctival injection) and
biomarker (hsCRP and SAA) responses in 24 hrs which was durable up
to 180 days. In contrast, canakinumab doses of 1 mg/kg i.v. without
induction were only durable up to 90 days. Support for more
sustained and higher dose canakinumab therapy was also seen in the
rheumatoid arthritis proof of concept study CACZ885A2101, where
higher doses of canakinumab were required (.gtoreq.3.0 mg/kg i.v.)
to achieve a significant clinical response as scored by the ACR
system. Furthermore, in the CACZ885A2102 study, analysis of gene
expression known to be related to IL-1.beta. expression,
inflammasome activity, and autoinduction of IL-1.beta., showed more
complete response to higher dose (10 mg/kg i.v.) than lower dose (1
mg/kg i.v.) canakinumab. In addition, IL-1.beta. and inflammasome
related gene expression modification began to decrease with the
lower dose (1 mg/kg i.v.) compared to the higher dose (10 mg/kg
i.v.) between 10 and 12 weeks. Similar results were obtained in a
canakinumab rheumatoid arthritis study where IL-1.beta. related
genes were suppressed more with 300 mg s.c. q2 weeks dosing than
150 mg q4 weeks dosing.
[0264] The documented safety record of canakinumab up to doses of
300 mg s.c. every 2 weeks with and without induction dose of 600 mg
i.v., in a study in rheumatoid arthritis patients up to 6 months,
300 mg q1month, in a study in gout patients up to 6 months, and 150
mg q1month, in a study in T2DM patients up to 4 months supports the
use of this higher dose regimen.
Rationale for Choice of Comparator
[0265] This trial is placebo controlled to provide robust evidence
on the effects of canakinumab on clinical events and safety as well
tolerability. No comparative anti-inflammatory treatment has been
shown to date to benefit patients with cardiovascular disease and
thus an active comparator arm is not available. All patients in all
treatment arms will receive standard of care post-MI background
therapy including, but not limited to, lipid lowering,
anti-hypertensive, beta blockers, and anti-platelet therapy as
appropriate.
TABLE-US-00002 TABLE 1 Study design ##STR00001## Months 15, 21, 27,
33 etc. are drug dispensing visits only and therefore not
displayed. .dagger. canakinumab 300 mg s.c. induction at
randomization (month 0) and week 2 (month 0.5), and then 300 mg
s.c. quarterly beginning at week 12.
[0266] Objectives of the study are the prevention or reduction of
risk of major adverse cardiovascular event (MACE) occurring during
the double-blind treatment period, which is a composite of CV
death, non-fatal MI, and stroke.
[0267] Other objectives are hospitalization for unstable angina
requiring unplanned, new onset type-diabetes among patients with
pre-diabetes at randomization, deep-vein thormbosis/pulmonary
embolism, Supraventricular tachycardia/atrial fibrillation, stent
thrombosis (probable or definite), hospitalization or prolongation
of hospitalization for heart failure, cardiovascular death,
non-fatal MI, stroke and all-cause mortality composite, major
coronary events composite (CHD death, non-fatal MI), total vascular
events composite, coronary revascularization procedures (PCI or
coronary artery bypass graft (CABG) and stroke by etiology
[0268] Patient reported outcomes (PRO) have been identified as
important in the post MI patient population. While a variety of
relevant concepts within the context of canakinumab have been
identified, the concepts of tiredness, physical function and
performance function have been selected as prioritized measurement
concepts. In order to measure these concepts a set of PRO
instruments will be administered.
[0269] The PRO instrument to be included in this trial, where
available, is the EQ-5D. Details on each of this instrument are
provided in addition to the target population in the sections
"General".
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Sequence CWU 1
1
81118PRThomo sapiens 1Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Val Tyr 20 25 30 Gly Met Asn Trp Val Arg Gln
Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ile Ile Trp Tyr
Asp Gly Asp Asn Gln Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu
Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Arg Asp Leu Arg Thr Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110 Leu Val Thr Val Ser Ser 115 2107PRThomo sapiens 2Glu
Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val Thr Pro Lys 1 5 10
15 Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Ser
20 25 30 Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu
Leu Ile 35 40 45 Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser
Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Asn Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Ala Tyr Tyr Cys
His Gln Ser Ser Ser Leu Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr
Lys Val Asp Ile Lys 100 105 35PRTHOMO SAPIENS 3Val Tyr Gly Met Asn
1 5 417PRTHOMO SAPIENS 4Ile Ile Trp Tyr Asp Gly Asp Asn Gln Tyr Tyr
Ala Asp Ser Val Lys 1 5 10 15 Gly 56PRTHOMO SAPIENS 5Asp Leu Arg
Thr Gly Pro 1 5 611PRTHOMO SAPIENS 6Arg Ala Ser Gln Ser Ile Gly Ser
Ser Leu His 1 5 10 76PRTHOMO SAPIENS 7Ala Ser Gln Ser Phe Ser 1 5
87PRTHOMO SAPIENS 8His Gln Ser Ser Ser Leu Pro 1 5
* * * * *
References